Dr. David Finlay
Associate Prof. in Immunometabolism, Biochemistry
Associate Prof. in Immunometabolism, Pharmacy
Manipulating immune responses has the potential to provide therapy for a wide range of diseases from autoimmunity to cancer. The serine/threonine kinase mTORC1 (mammalian Target of Rapamycin complex 1) is a key regulator of immune cell function: inhibition of mTORC1 in T cells promotes regulatory T cell responses while inhibition of mTORC1 in dendritic cells (DC) promotes a more proinflammatory DC phenotype. Therefore, mTORC1 signalling has diverse roles in immune cell subsets and is potentially a crucial therapeutic target for manipulating immune responses.
mTORC1 is key to the regulation of various aspects of cellular metabolism: energy metabolism, lipid synthesis and autophagy. Our recent research in CD8 T cells and Natural Killer (NK) cells links mTORC1-regulated glycolysis to the control of fundamental effector functions and thus promotes the idea that mTORC1 signaling integrates the control of cellular metabolism and immune cell function.
Our research is further characterising the links between mTORC1 controlled metabolism and T cell, Natural Killer (NK) cell and DC function.
Ongoing projects are investigating:
- Deciphering the mTORC1 dependent mechanisms controlling dendritic cell metabolism and function
- Investigating metabolic regulation of NK cell function.
- Characterising the role of mTORC1/Srebp signaling in directing function NK cells.
Current research Students:
Postdoctoral Research Scientists:
Dr Nadine Assmann
Marie Curie Fellowship Career Integration Grant (321603), Science Foundation Ireland Project Grant (12/IP/1286), Science Foundation Ireland Career Development Award (13/CDA/2161), Science Without Borders (Brazil) PhD programme. Wellcome Trust/NIH PhD programme, Irish Cancer Society.
I first became captivated by the complexities of cellular signal transduction pathways during my undergraduate biochemistry degree at Trinity College Dublin, which led me to a PhD at the University of Dundee investigating roles for protein kinases such as mTORC1 in the control of metabolic pathways in hepatocytes. I retained a keen interest in protein kinase signalling during my postdoctoral research in Prof. Doreen Cantrell's lab at the University of Dundee. It was during this time in I realised that mTORC1 is a key regulator of CD8 T cell biology largely because it controls cellular metabolic pathways. This research led to one of the first publications in the then emerging field of immunometabolism and motivated me to establish my independent research group to further explore how cellular metabolism is linked to the control of immune cell fate and function. Since 2011, I have secured in excess of 3.4 million research funding and my research has contributed significantly to the current understanding that cellular metabolism is integrally linked to immune cell functions.
My research is at the forefront of the Immunometabolism field and I have published high impact studies that have challenged established dogmas. My research group was the first to characterize cellular metabolic pathways in Natural Killer cells to show that the way they metabolize glucose is different to the metabolic pathways described in biochemistry textbooks (Journal of Immunology 2014, Nature Immunology 2017, Nature Communications 2018). My research has also made key contributions to an emerging idea that nutrients are more than just fuels and function as important signals; we showed that glucose controls signal transduction pathways in Dendritic cells (DC) to inhibit DC functions and to limit the induction of CD8 T cell responses (Nature Communications 2017). My contribution to leading this new field of immunometabolism have been recognised with invitations to write review articles for high impact journals including the Journal of Clinical Investigation (2016), Seminars in Immunology (2017) and Nature Reviews Immunology (2019, which have been well received and highly cited.
In 2017 I secured an ERC Consolidator Award to study nutrients as key determinants of DC-induced CD8 T cell responses. Successful implementation of this ERC research programme will open new horizons for the study of nutrients as determinants of immune responses. Based on my expertise in the area of lymphocyte metabolism, it is my ambition that this ERC research programme will lead me to further ground-breaking studies assessing the role for nutrients in controlling T cell and NK cell responses in diverse inflammatory situations.
Publications and Further Research Outputs
Elisabeth Littwitz-Salomon Diana Moreira Joe N. Frost Chloe Choi Kevin T. Liou David K. Ahern Simon O'Shaughnessy Bernd Wagner Christine A. Biron Hal Drakesmith Ulf Dittmer David K Finlay , Metabolic requirements of NK cells during the acute response against retroviral infection, Nature Communications, 2021, pIn press-
Jones N, Blagih J, Zani F, Rees A, Hill DG, Jenkins BJ, Bull CJ, Moreira D, Bantan AIM, Cronin JG, Avancini D, Jones GW, Finlay DK, Vousden KH, Vincent EE, Thornton CA, Fructose reprogrammes glutamine-dependent oxidative metabolism to support LPS-induced inflammation, Nature Communications, 22, (12), 2021, p1209-
Slattery K , Woods E , Zaiatz-Bittencourt V, Marks S , Chew S , Conroy M , Goggin C, MacEochagain C, Kennedy J, Lucas S , Finlay DK , Gardiner CM, TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer, Journal for Immunotherapy of Cancer , 9, (2), 2021
Dowling JK, Afzal R, Gearing LJ, Cervantes-Silva MP, Annett S, Davis GM, De Santi C, Assmann N, Dettmer K, Gough DJ, Bantug GR, Hamid FI, Nally FK, Duffy CP, Gorman AL, Liddicoat AM, Lavelle EC, Hess C, Oefner PJ, Finlay DK, Davey GP, Robson T, Curtis AM, Hertzog PJ, Williams BRG, McCoy CE , Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages, Nature Communications, 12, (1), 2021, p1460-
Katie L. O'Brien, Nadine Assmann, Eimear O'Connor, Cathal Keane, Jessica Walls, Chloe Choi, Peter J. Oefner, Clair M. Gardiner, Katja Dettmer, David K. Finlay, De novo polyamine synthesis supports metabolic and functional responses in activated murine Natural Killer cells, European Journal of Immunology, 2020
Chloe Choi and David K. Finlay, Diverse Immunoregulatory Roles of Oxysterols-the Oxidized Cholesterol Metabolites, Metabolites, 10, (10), 2020, pE384-
Jessica F. Walls, Jeff J. Subleski, Erika M. Palmieri, Marieli Gonzalez Cotto, Clair M. Gardiner, Daniel W. McVicar, David K. Finlay, Metabolic but not transcriptional regulation by PKM2 is important for Natural Killer cell responses, eLIFE, 2020
Jones N, Vincent EE, Cronin JG, Panetti S, Chambers M, Holm SR, Owens SE, Francis NJ, Finlay DK, Thornton CA, Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation, Nature Communications, 10, (1), 2019, p2042-
Finlay, D.K., N-myristoylation of AMPK controls T cell inflammatory function, Nature Immunology, 20, (3), 2019, p252-254
Nidhi Kedia-Mehta and David. K Finlay, Competition for nutrients; an emerging role in controlling immune responses, Nature Communications, 10, (1), 2019, p2123-
Nidhi Kedia-Mehta, Chloe Choi, Aisling McCrudden, Elisabeth Littwitz-Salomon, Proinnsias G. Fox, Clair M. Gardiner, and David. K Finlay, Natural Killer cells integrate signals received from tumour interactions and IL2 to induce robust and prolonged anti-tumour and metabolic responses, Immunmetabolism, (2), 2019, pe190014
Katie O'Brien and David. K Finlay, Immunometabolism and Natural Killer cell responses, Nature Reviews Immunology, 19, (5), 2019, p282 - 290
O'Brien A, Loftus RM, Pisarska MM, Tobin LM, Bergin R, Wood NAW, Foley C, Mat A, Tinley FC, Bannan C, Sommerville G, Veerapen N, Besra GS, Sinclair LV, Moynagh PN, Lynch L, Finlay DK, O'Shea D Hogan AE, Obesity Reduces mTORC1 Activity in Mucosal-Associated Invariant T Cells, Driving Defective Metabolic and Functional Responses, Journal of Immunology, 202, (12), 2019, p3404 - 3411
Loftus, R.M. and Assmann, N. and Kedia-Mehta, N. and O'Brien, K.L. and Garcia, A. and Gillespie, C. and Hukelmann, J.L. and Oefner, P.J. and Lamond, A.I. and Gardiner, C.M. and Dettmer, K. and Cantrell, D.A. and Sinclair, L.V. and Finlay, D.K., Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice, Nature Communications, 9, (1), 2018
Zaiatz-Bittencourt, D.K. Finlay, C.M. Gardiner. , Canonical TGF signalling pathway represses human NK cell metabolism, Journal of Immunology, 200, (12), 2018, p3934 - 3941
David, J. and O'Toole, E. and O'Reilly, K. and Thuery, G. and Assmann, N. and Finlay, D. and Harkin, A., Inhibitors of the NMDA-Nitric Oxide Signaling Pathway Protect Against Neuronal Atrophy and Synapse Loss Provoked by L-alpha Aminoadipic Acid-treated Astrocytes, Neuroscience, 392, 2018, p38-56
Michelet X, Dyck L, Hogan A, Loftus LM, Duquette D, Wei K, Beyaz S,Tavakkoli A, Foley C, Donnelly R, O'Farrelly C, Raverdeau M, Vernon A, Pettee W, O'Shea D, Nikolajczyk BS, Mills KH, Brenner MB, Finlay DK and Lynch L, Metabolic reprogramming of natural killer cells in obesity prevents cytotoxicity and promotes tumor progression, Nature Immunology, 19, (12), 2018, p1330 - 1340
Nadine Assmann, Katie L. O'Brien, Raymond P. Donnelly, Lydia Dyck, Vanessa Zaiatz-Bittencourt, Róisín M. Loftus, Paul Heinrich, Peter J. Oefner, Lydia Lynch, Clair M. Gardiner, Katja Dettmer & David K. Finlay, Srebp-controlled glucose metabolism is essential for NK cell functional responses, Nature Immunology, 18, (11), 2017, p1197 - 1206
Shehata HM, Murphy AJ, Lee MKS, Gardiner CM, Crowe SM, Sanjabi S, Finlay DK, Palmer CS, Sugar or Fat?-Metabolic Requirements for Immunity to Viral Infections, Frontiers in Immunology, 8, 2017, p1311-
Simon J. Lawless, Nidhi Kedia-Mehta, Jessica F. Walls, Ryan McGarrigle, Orla Convery, Linda V. Sinclair, Maria N. Navarro, James Murray, David K. Finlay, Glucose represses dendritic cell-induced T cell responses, Nature Communications, (8), 2017, p15620-
Clair M. Gardiner and David K. Finlay, What Fuels Natural Killers? Metabolism and NK Cell Responses, Frontiers in Immunolobgy, 8, 2017
Tobin, Laura M and Mavinkurve, Meenal and Carolan, Eirin and Kinlen, David and O'Brien, Eoin C and Little, Mark A and Finlay, David K and Cody, Declan and Hogan, Andrew E and O'Shea, Donal, NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient, JCI insight, 2, (24), 2017, pe94939
Loftus RM, Finlay DK, Immunometabolism; cellular metabolism turns immune regulator., Journal of Biological Chemistry, 291, (1), 2016, p1 - 10
Walls J, Sinclair L, Finlay D, Nutrient sensing, signal transduction and immune responses., Seminars in Immunology, 28, (5), 2016, p396-407
Viel S, Marçais A, Guimaraes FS, Loftus R, Rabilloud J, Grau M, Degouve S, Djebali S, Sanlaville A, Charrier E, Bienvenu J, Marie JC, Caux C, Marvel J, Town L, Huntington ND, Bartholin L, Finlay D, Smyth MJ, Walzer T, TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway., Science Signalling, 9, 2016, pra19-
Keating SE, Zaiatz-Bittencourt V, Loftus RM, Keane C, Brennan K, Finlay DK, Gardiner CM., Metabolic Reprogramming Supports IFN-γ Production by CD56bright NK Cells., Journal of Immunology, 196, (6), 2016, p2552 - 2560
Assmann N, Finlay DK., Metabolic regulation of immune responses: therapeutic opportunities., Journal of Clinical Investigation, 126, (6), 2016, p2031 - 2039
David Finlay, Glucose, glycolysis and lymphocyte responses., Molecular Immunology, 2015
David Finlay, Starved human T lymphocytes keep fighting., European Journal of Immunology, 2015
Donnelly, R.P., Loftus, R.M., Keating, S.E., (...), Gardiner, C.M., Finlay, D.K., MTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function, Journal of Immunology, 193, (9), 2014, p4477-4484
David Finlay, IRF4 links antigen affinity to CD8(+) T-cell metabolism., Journal of Immunology and Cell Biology , 92, 2014, p6 - 7
Zarrouk M, Finlay DK, Foretz M, Viollet B, Cantrell DA, Adenosine-mono-phosphate-activated protein kinase-independent effects of metformin in T cells., PloS one, 9, (9), 2014, pe106710
Rolf J, Zarrouk M, Finlay DK, Foretz M, Viollet B, Cantrell DA., AMPKα1: A glucose sensor that controls CD8 T-cell memory., European Journal of Immunology, 43, (4), 2013, p889-96
David K. Finlay, Ella Rosenzweig, Linda V. Sinclair, Carmen Feijoo-Carnero, Jens L. Hukelmann, Julia Rolf, Andrey A. Panteleyev, Klaus Okkenhaug, Doreen A. Cantrell, PDK1 regulation of mTOR and Hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells, Journal of Experimental Medicine, 209, (13), 2012, p2441 - 2453
David K Finlay, Regulation of glucose metabolism in T cells: new insight into the role of phosphoinositide 3-kinases, Frontiers in Immunology, 3, 2012, p247-
Finlay DK, Cantrell DA, Metabolism, migration and memory in cytotoxic T cells, Nature Reviews Immunology, 11, (2), 2011, p109 - 117
Finlay D, Cantrell D, The coordination of T-cell function by serine/threonine kinases., Cold Spring Harbor perspectives in biology, 3, (1), 2011, pa002261
Macintyre A, Finlay DK, Preston G, Sinclair LV, Waugh CM, Tamas P, Feijoo C, Okkenhaug K, Cantrell DA, Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism, Immunity, 34, (2), 2011, p224 - 236
Finlay DK, Cantrell DA, The co-ordination of T cell function by Serine/threonine kinases, Cold Spring Harbour Perspectives in Biology, 3, (1), 2011
Finlay DK, Cantrell DA, Phosphoinositide 3-kinase and the mammalian target of rapamycin pathways control T cell migration., Annals of the New York Academy of Sciences, 1183, 2010, p149-57
Finlay DK, Kelly AP, Clarke R, Sinclair LV, Deak M, Alessi DR, Cantrell DA, Temporal differences in the dependency on Phosphoinositide dependent kinase 1 distinguish the development of Vα14 iNKT cells, regulatory T cells and conventional T cells, Journal of Immunology, 185, (10), 2010, p5973 - 5982
Tamás P, Macintyre A, Finlay D, Clarke R, Feijoo-Carnero C, Ashworth A, Cantrell D, LKB1 is essential for the proliferation of T cell progenitors and mature peripheral T cells, European Journal of Immunology, 40, (1), 2010, p242 - 253
Waugh C., Sinclair LV., Finlay DK., Bayascas J., Cantrell DA., Phosphoinositide (3,4,5)-triphosphate binding to phosphoinositide-dependent kinase 1 regulates a protein kinase B/Akt signaling threshold that dictates T-cell migration, not proliferation, Molecular Cellular Biology, 29, (21), 2009, p5952 - 5962
Finlay DK., Sinclair LV., Fejoo C., Waugh C., Hagenbeek TJ., Spits H., Cantrell DA. , Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes, Journal of Experimental Medcine, 206, (11), 2009, p2441 - 2454
Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, Knight ZA, Cobb BS, Cantrell D, O'Connor E, Shokat KM, Fisher AG, Merkenschlager M., T cell receptor signaing controls Foxp3 expression via PI3K, Akt and mTOR., PNAS, 105, (22), 2008, p7797 - 7802
Sinclair LV., Finlay D., Fejoo C., Cornish GH., Gray A., Ager A., Okkenhaug K., Hagenbeek TJ., Spits H., Cantrell DA, Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking, Nature Immunology, 9, (5), 2008, p513 - 521
Kelly AP., Finlay DK., Hinton HJ., Clarke RG., Fiorini E, Radtke F., Cantrell DA, Notch-induced T cell development requires phosphoinositide-dependent kinase 1, EMBO Journal, 26, (14), 2007, p3441 - 3450
Finlay D., Ruiz-Alcaraz AJ., Lipina C., Perrier S., Sutherland C, A temporal switch in the insulin-signalling pathway that regulates hepatic IGF-binding protein-1 gene expression, Journal of Molecular Endocrinology, 37, (2), 2006, p227 - 237
Liu HK, Perrier S, Lipina C, Finlay D, McLauchlan H, Hastie CJ, Hundal HS, Sutherland C, Functional characterisation of the regulation of CAAT enhancer binding protein alpha by GSK-3 phosphorylation of Threonines 222/226, BMC Molecular Biology, 7, (14), 2006
Lipina C., Huang X., Finlay D., McManus EJ., Alessi DR., Sutherland C, Analysis of hepatic gene transcription in mice expressing insulin-insensitive GSK3, Biochemical Journal, 392, (3), 2005, p633 - 639
Finlay D., Patel S., Dickson L.M., Shapiro N., Marquez R., Rhodes C.J., Sutherland C., Glycogen synthase kinase-3 regulates IGFBP-1 gene transcription through the thymine-rich insulin response element, BMC Molecular Biology, 5, (15), 2004
David K Finlay, Nutrients and metabolites controlling NK cell responses , European Federation of Immunological Societies in tour, Online via Zoom, 19 Feb, 2021, EFIS
David K Finlay, Nutrients and metabolites controlling lymphocyte responses , ImmunoMetNet meeting, Online via Zoom, 8 April, 2020, Jan van den Bossche
David K Finlay, Metabolism and NK cell anti-tumour responses , Immunometabolism, from bench to bedside, Online via Zoom (Copenhagen), 8th September, 2020, University of Copenhagen PhD programme
David K Finlay, What fuels Cancer Killers, Cambridge Scientific Society Seminar series, Cambridge, UK, 2020, Cambridge Scientific Society (Student society)
David K Finlay, Cancer and Natural Killer cell metabolism intertwined, Abcam Cancer Metabolism conference, Online via Zoom (Cambridge), 15th June, 2020, Abcam
David K Finlay, Nutrients and metabolites controlling lymphocyte responses , Seminar, Centro de Biología Molecular Severo Ochoa, 28 Feb, 2020, Centro de Biología Molecular Severo Ochoa
David K Finlay, Shaping immune responses by targeting Immunometabolism , British Transplantation Society conference, Belfast, 5 March, 2020
David Finlay, Metabolic regulation of NK cell responses, Seminar, University of Dundee, 8th Feburary, 2019, Prof Doreen Cantrell
David Finlay, Metabolic regulation of NK cell responses, IACR annual conference, Belfast, 21st Feburary, 2019
David Finlay, Metabolic Regulation of NK cell responses, Immunometabolism: Fundamentals to Prospective New Therapies , Boston, 25th June, 2019, Abcam, Prof Luke O'Neill
David Finlay, Metabolic regulation of NK cell responses, Fuelling the immune response: UK immunometabolism meeting 2019, Newcastle, 14th March, 2019, British Society for Immunology's Immunometabolism Affinity Group
David Finlay, Metabolic regulation of Natural Killer cell anti-tumour responses, Seminar, Newcastle University, 13th March, 2019, Dr Kevin Marchbank
David Finlay, NK cell metabolism; Implications for anti-tumour responses, Seminar, Imperial College London, 13th May, 2019, Prof Adam Byrne
David K Finlay, What fuels NK cells to destroy tumours?, Trinity Biomedical Frontiers Series, Trinity Biomedical Sciences Institute, 2018
David Finlay, cMyc and Srebp drive glucose fueled Natural Killer responses, Translational Immunometabolism', Cell Press Sympsium, Basel, Switzerland, 24th June, 2018
David Finlay, Metabolic regulation of NK cell anti-tumour responses, Natural Killer Cell Symposium 2018 - of the German Society for Immunology , Hamburg, Germany, 10th September, 2018, Keynote Speaker
David Finlay, Fueling Robust Anti-Tumor NK Cell Responses , Discovery on Target Conference; NK cell based Cancer Immunotherapies, Boston, 26 September, 2018
David Finlay, Metabolic regulation of Immune responses., Institute Seminar Series, University of Lausanne, 21st November, 2018, Ping-Chih Ho
David Finlay, What fuels Natural Killer Cell anti-tumour responses., Institute Seminar Series, University of Dundee, 28th Feburary, 2018
David Finlay, What fuels Natural killer cell anti-tumour responses, Centre d'Etude des Pathologies Respiratoires (CEPR) -Institute Seminar, Tours, France, 29th May, 2018, Centre d'Etude des Pathologies Respiratoires (CEPR)
David K Finlay, What fuels Natural Killer cells against Cancer, Trinity Week Symposium , Exam Hall, TCD, 2018
David Finlay, Glucose in the regulation of DC-induced CD8 T cell responses, Institute Seminar Series, Department of Pathology, University of Cambridge, 8th November, 2017
David Finlay, Srebp-controlled glucose metabolism is essential for NK cell functional response, Microbes, Immunity and Metabolism, Paris, France, 16th November , 2017, Instituit Pasteur
David Finlay, Srebp-controlled glucose metabolism is essential for NK cell functional response, Annual meeting of the French Society for Immunology, Reims, France., 9th November , 2017
David K Finlay, A distinct engine configuration, controlled by a switch called Srebp, powers our Natural Killers against cancer , Cancer Research Frontiers, Trinity Biomedical Sciences Institute, 2017
David Finlay, What fuels Natural Killers? Metabolic regulation of NK cells, Institute Seminar, Heinrich Pette Institute, Hamburg, Germany, April, 2017
David Finlay, Glucose represses Dendritic Cell-induced T cell responses, Institute Seminar, Medical University of Vienna, Institute of Medical GeneticsUniversity of , 6th December, 2016, Thomas Weichhart, PhD
David Finlay, Metabolic regulation of Natural Killer Cells , American Association of Immunology (AAI), New Orleans, 9 May, 2015
David Finlay, Metabolic regulation of natural killer cells, Biochemical Society Transactions, 43, (4), 2015, p758 - 762.
David K Finlay, Food fight, Immune cells vs Cancer, Trinity Biomedical Frontiers Series, Trinity Biomedical Sciences Institute, 2015, School of Biochemistry and Immunology
David Finlay, Nutrients control immune responses , Irish Society of Immunology, Trinity College Dublin, September , 2015
David Finlay, Glucose and glycolysis are anti-inflammatory in Dendritic cells , 111th International Titisee Conference, Titisee, Germany, April, 2015
Finlay DK, mTORC1 regulates CD8+ T-cell glucose metabolism and function independently of PI3K and PKB., Biochemical Society transactions, 41, (2), 2013, p681-6
Finlay DK, Cantrell DA, The role of PKB in CD8 T cells - Dogma versus Reality, . Keystone Symposia on PI-3-Kinase Signalling Pathways, Keystone, Colorado, USA, Feb, 2011
DescriptionOur immune system is important for our health protecting us from infection/cancer, but inappropriate immune responses cause us harm. Diverse diseases could be treated through therapeutic manipulation of our immune systems. My research group wants to understand how to control immune cells and is now revealing the importance of cellular metabolism. Our research shows that the cellular fuels available to immune cells and the ways that these fuels are used have a big impact on their function. We are revealing novel strategies to modulate immune cell function through targeting cellular metabolism and new therapeutic opportunities are being explored. Our data show following activation Natural killer (NK) cells, lymphocytes with important anti-cancer functions, undergo a robust metabolic response leading to elevated levels of glycolysis and oxidative phosphorylation. We have identified the key metabolic regulators of this metabolic response to be mTORC1, cMyc and Srebp. Directly disrupting metabolic pathways in NK cells or interfering with the function of these metabolic regulators severely inhibits NK cell anti-cancer functions; IFN-gamma production, granzyme b expression and tumour cell killing. We are exploring how NK cell metabolism might be manipulated to improve NK cell-based anti-cancer immunotherapies. In contrast to lymphocytes, mTORC1 and glucose metabolism actually inhibit the function of Dendritic Cells (DC). We made the novel discovery that starving DC of glucose results in increased proinflammatory outputs and enhanced DC-induced T cell responses. This study highlights the complex relationship between nutrient availability and the induction of immune responses. An important next step will be investigating the distribution of nutrients in vivo, to determine which immune cells are nutrient replete and those that are deprived of nutrients. Ongoing projects include: --Investigating nutrients as key determinants of DC-induced CD8 T cell responses (funded by ERC-CoG) --Characterising metabolic networks in activated NK cells and how they facilitate anti-tumour NK cell functions.(funded by SFI)
- Investigating nutrients as key determinants of DC-induced CD8 T cell responses
- A new immunoregulatory axis has emerged in recent years demonstrating that cellular metabolism is crucial in controlling immune responses. This regulatory axis is acutely sensitive to nutrients that fuel metabolic pathways and support nutrient sensitive signalling pathways. My recent research demonstrates that nutrients are dynamically controlled and are not equally available to all immune cells. The data shows that activated T cells, clustered around a dendritic cell (DC), can consume the available nutrients, leaving the DC nutrient deprived in vitro. This local regulation of the DC nutrient microenvironment by neighbouring cells has profound effects on DC function and T cell responses. Nutrient deprived DC have altered signalling (decreased mTORC1 activity), increased pro-inflammatory functions (IL12 and costimulatory molecule expression) and induce enhanced T cell responses (proliferation, IFN production). However, proving this, particularly in vivo, is a major challenge as the tools to investigate nutrient dynamics within complex microenvironments have not yet been developed. This research programme will generate innovative new technologies to measure the local distribution of glucose, glutamine and leucine (all of which control mTORC1 signalling) to be visualised and quantified. These technologies will pioneer a new era of in vivo nutrient analysis. Nutrient deprivation of antigen presenting DC will then be investigated (using our new technologies) in response to various stimuli within the inflammatory lymph node and correlated to CD8 T cell responses. We will generate state-of-the-art transgenic mice to specifically knock-down nutrient transporters for glucose, glutamine, or leucine in DC to definitively prove that the availability of these nutrients to antigen presenting DC is a key mechanism for controlling CD8 T cells responses. This would be a paradigm shifting discovery that would open new horizons for the study of nutrient-regulated immune responses.
- Funding Agency
- Date From
- April 2018
- Date To
- March 2023
- Investigating Natural Killer (NK) cell metabolism as a determinant of NK cell anti-tumour activity
- Effective anti-tumour immune responses rely upon key effector immune cells, such as Natural Killer (NK) cells, sustaining their anti-tumour activity within the inhospitable tumour microenvironment. Our initial data suggest that NK cell glucose metabolism is closely linked to key anti-tumour functions. Activated NK cells that cannot maintain elevated glycolysis do not sustain the expression of key anti-tumour molecules, IFNγ and granzyme B. This data provides a new perspective to explain defective NK cell function within the tumour microenvironment. We hypothesise that the tumour microenvironment represses NK cell anti-tumour functions by disrupting NK cell metabolism. This project will fully characterise the relationship between NK cell metabolism and function and investigate the mechanisms involved using state-of-the-art technologies including various transgenic mouse models. Central to this research will be the identification of novel metabolic biomarkers, using mass spectrometry-based proteomics, that accurately report on NK cell metabolism and thus NK cell anti-tumour functions. These analytical tools will allow the effect of the tumour microenvironment on NK metabolism and function to be accurately monitored in vivo, but will also have widespread applications in pathological diagnostics and prognostics that will ultimately lead to enhanced patient management.
- Funding Agency
- Science Foundation Ireland
- Date From
- Date To
- Characterising the role of mammalian Target Of Rapamcyin Complex 1 (mTORC1)/Srebp1c signaling in directing the differentiation and function of T cell subsets.
- Modulating immune responses by shifting the balance of effector versus regulatory/memory T cells has significant potential as a therapy for various autoimmune diseases and preventing organ transplant rejection. The mammalian Target Of Rapamycin Complex1 (mTORC1) has diverse effects in T cells and dictates T cell fate. mTORC1 inhibition provides potent immunosuppression but is associated with significant toxicity. Dissecting the mechanisms that account for the multiple mTORC1 effects on T cell differentiation would allow for the design of therapies that provide desirable immunomodulation with less toxicity. Recent data suggests mTORC1 integrates the control of T cell glucose metabolism and differentiation by controlling the HIF1 transcription factor complex. mTORC1 also regulates lipid metabolism through the control of Srebp1c, though this has not been investigated in T cells. Given that lipid metabolism has also been linked to the control of T cell fate, it seems crucial to comprehensively study the role of mTORC1/Srebp1c signalling in T cells. Preliminary data confirms mTORC1 dependent Srebp1c expression and activity in T cells. This project aims to study mTORC1/Srebp1c with respect to lipid metabolism, differentiation and function of T cells. This will be achieved using pharmacological and genetic approaches and using state of the art in vivo technologies.
- Funding Agency
- Science Foundation Ireland
- Date From
- Date To
- Investigating the impact of cholesterol on anti-tumour NK cell responses.
- Cancer immunotherapy is being heralded as the most important advances in cancer therapy since the discovery of the first chemotherapeutic agents. A growing number immunotherapeutic strategies demonstrate how the immune system can eradicate tumours once it is given appropriate instruction. It is well established that NK cells have important roles in the anti-tumour effect of immunotherapeutic strategies. It is therefore imperative to understand factors that might affect the ability of cancer patients NK cells to mount a robust anti-tumour response during the course of cancer immunotherapy. Dr Finlay's research has demonstrated the importance of NK cell metabolism in facilitating robust NK cell responses. NK cells that cannot up-regulate rates of glucose metabolism have reduced expression of key effector molecules. Furthermore, recent data argue that elevated levels of cholesterol and oxidised cholesterol derivatives (oxysterols) prevent the up-regulation cellular glucose metabolism in activated NK cells and the acquisition of normal NK cell effector function. Dr Finlay's research suggests that this effect of cholesterol/oxysterols is mediated by the ability of these sterol molecules to inhibit the action of the Srebp transcription factors. This preliminary data has lead us to the hypothesis that cholesterol/oxysterol mediated inhibition of Srebp transcription factors limits NK cell metabolism and represses the NK cell anti-tumour response. This project will robustly test this hypothesis using complementary pharmacological and mouse transgenics approaches and combined with detailed biochemical analyses and murine tumour models. The key findings will be validated in human NK cells isolated from PBMC of healthy donors. Through a collaboration with Dr Hogan at St Vincent's hospital, serum samples from patients with high levels of cholesterol will be collected. The effect of these serum samples on NK cell on metabolism and NK cell effector function will be investigated. Through these robust scientific approaches, we aim to establish the effect of cholesterol/oxysterols on NK cell anti-tumour responses. If validated, this novel mechanism to control NK cell responses has important implications for the treatment of cancer patients. The data would suggest that the management of patients cholesterol levels should precede the initiation of cancer immunotherapy. Altering patient management in this way could potentially lead to significant increases the efficacy of diverse cancer immunotherapeutic approaches.
- Funding Agency
- Irish Cancer Society
- Date From
- Date To
- Investigating 25-hydroxycholesterol as a novel regulator of Natural Killer cell anti-tumour responses.
- Natural Killer (NK) cells are important in our bodies defence against cancer. They are lymphocytes with the ability to detect and directly kill tumour cells. However, in cancer patients NK cells are often found to be dysfunctional. Dr Finlay's lab has recently made the discovery that activated NK cells show dramatic changes in the way that they metabolise glucose that are essential for their functions including the ability to kill cancer cells. A key and highly novel finding was that the key regulator of this metabolic response is a factor called Sterol regulatory element binding protein, or Srebp. When Srebp is blocked, NK cells cannot undergo these metabolic changes and they fail to kill tumour cells in the lab and in a mouse model of melanoma (Assmann et al, Nat. Immunol. 2017). Srebp can be blocked by cholesterol and in particular by the cholesterol-like molecule called 25-hydroxysterol (25HC). This research has revealed a completely novel way to control anti-tumour NK cell functions through regulating the activity of Srebp. Cancer cells have been described to produce and secrete 25HC. Additionally, activated macrophages express high amounts of the enzyme that makes 25HC, and macrophage-derived 25HC is emerging as important in the regulation of inflammatory responses. In addition, 25HC levels are elevated in individuals with high blood cholesterol levels (hypercholesterolemia). This project will investigate the impact of 25HC produced by macrophages, tumour cells or due to a high cholesterol diet, on NK cell metabolic and functional responses. This will be achieved using various cutting-edge approaches including metabolic analyses and tumour cytotoxicity assays. NK cells functions will also be monitored in mice fed a high cholesterol diet. This project will increase our understanding of the control of NK cell anti-tumour functions and provide important insight into why NK cells are dysfunctional in cancer patients.
- Funding Agency
- Irish Research Council
- Date From
- Date To
- Investigating the role for PKM2 for NK cell responses.
- Natural Killer (NK) cells have an important role in immune responses to viruses and tumours. Integrating changes in signal transduction pathways and cellular metabolism is essential for effective NK cells responses. The PKM2 isoform of the glycolytic enzyme Pyruvate Kinase Muscle has described roles in regulating glycolytic flux and signal transduction, especially gene transcription. While PKM2 expression is robustly induced in activated NK cells, mice lacking PKM2 in NK cells showed no defect in NK cell metabolism or anti-viral responses to MCMV infection. This maintenance of function is explained by compensatory PKM1 expression in PKM2-null NK cell cells demonstrating that PKM2 is not a signalling molecule in this immune cell type. To further investigate the role of PKM2 we forced the tetramerization of the protein with TEPP-46, which increases its catalytic activity while inhibiting any signalling functions mediated by mono/dimeric conformations. NK cells activated with TEPP-46 had reduced effector function due to TEPP-46-induced increases in oxidative stress. Overall, PKM2-regulated glycolytic metabolism and redox status, not transcriptional control, facilitate optimal NK cells responses.
- Funding Agency
- Wellcome Trust
- Date From
- Date To
- Investigation of the Nutrient Requirements of DCs in vivo
- Dendritic cells (DCs) are the main sentinels of the immune system that patrol the body, scavenging for danger signals. Upon identifying a threat, they become activated and hone to immune organs (Eg. Spleen and Lymph Nodes) to orchestrate an immune response. Recent work has demonstrated that DCs are highly energetic cells, that utilize nutrients available in their environment to fuel their activation and function. Tissue culture studies have shown that DCs are highly sensitive to nutrient availability, identifying nutrients as key regulators of DC function. Despite these advancements there is a clear absence of information of how nutrients regulate DCs in living organisms. This project aims to address this dearth of knowledge by investigating the molecular machinery by which DCs take up and use nutrients. In particular, this work will for the first time, identify the nutrient transporters used by different types of DCs from immune organs. Classification of these transporters will provide valuable insight into the nutrient requirements of DCs and allow the identification of novel nutrient targets for therapeutic exploitation. This proposal will examine how the absence of specific nutrients effects the ability of DCs to orchestrate a correct immune response. Furthermore, the ability of DCs, which artificially lack nutrient receptors, to mount a response against a disease model will be assessed. This work will offer new insights into how nutrients regulate DC function under physiological conditions. These observations will provide a new and innovative method to manipulate DC function by targeting DC nutrient uptake. Due to central role of DCs in orchestrating an immune response the therapeutic implication of these findings is broad. Nutrient regulation of DC function could have a profound impact on vaccination design, infection and cancer therapies.
- Funding Agency
- Irish Research Council
- Date From
- Date To
- Regulation of NK Cells via cDC1-Derived 27-Hydroxycholesterol
- This immune system is regulated through a number of excitatory and inhibitory interactions between its cells. These include a number of intercellular interactions involving cell surface and secretory proteins. Recently it has been shown that immune cells require certain metabolic configurations to support their effector function. In the case of natural killer(NK) cells this involves a higher rate of glycolysis and oxidative phosphorylation which is supported by the targets of sterol regulatory element binding protein (Srebp) transcription factors. Cytokine-stimulated NK cells have increased expression of Srebp which supports a more robust immune response. Activation of Srebp is controlled by cholesterol and oxidised derivatives of cholesterol called oxysterols. These include 25-hydroxycholesterol (25HC) and 27-hydroxycholesterol (27HC). Therefore, through increased synthesis of oxysterols many cancers can use their metabolic configuration to dampen the immune response and promote immune evasion.Recent work has shown the the expression of Cyp27a1 (the enzyme that synthesises 27HC), is abundantly expressed in type 1 classical dendritic cells (cDC1). These are antigen expressing cells that are found in close proximity to CD8+T cells and NK cells in the spleen. This is because NK cells are a major source of the chemokine Xcl1 which binds to the Xcr1 receptor on the surface of the cDC1. Considering the close proximity of these cells in the spleen and the high expression of Cyp27a1 by cDC1, this project will investigate the Cyp27a1-27HC-Srebp signalling axis. If the hypothesis proves to be correct, this would reveal a new metabolic inhibitory signalling pathway between immune cells. This would be made possible using a number of techniques such as cytotoxicity assays, RNAseq, flow cytometry, confocal microscopy, live cell imaging and animal experiments.
- Funding Agency
- Irish Research Council
- Date From
- Date To
- Metabolic reprogramming and engineering of NK cells for improved cancer therapy
- Developing cellular immunotherapies for treating cancer promises to be the next great breakthrough in cancer therapy. NK cells are emerging as the preferred choice of cytotoxic lymphocyte for this purpose. However, the adverse conditions associated with the tumour microenvironment are limiting the effectiveness of these cells to treat cancer patients. The Finlay research team has demonstrated the importance of NK cellular metabolism for the cytotoxic anti-tumour functions of these cells. With our expertise we aim to metabolically enhance NK cells to provide superior anti-tumour responses when transferred into cancer patients.
- Funding Agency
- Enterprise Ireland
- Date From
- 17 June 2021
- Date To
- 16 June 2023
Established an Immunometabolism Forum to support immunologists and foster collaboration. Hosts >80 attendees from multiple Schools in TCD, and from RCSI and NUIM. Sponsorship secured from Agilent
Editorial Board for "Immunometabolism" Journal
Expert reviewer for Funding agencies including the Wellcome Trust, MRC, BBSRC, Netherlands Organisation for Scientific Research (NWO) and ERC Starter and Advanced grants
Expert reviewer for high impact scientific journals including Science, Nature Medicine, Nature Immunology, Cell Metabolism.
Awards and Honours
European Research Council Consolidator Award
Science Foundation Ireland - Career Development Award
Marie Sklodowska Curie - Career Integration Fellowship
Irish Society of Immunology
British Society of Immunology
TCD Students Biochemical Society